EnBrace HR for Depression Treatment and Prevention in Women Trying to Conceive and Early Pregnancy

Major depressive disorder (MDD) occurs twice as often in women as in men, with an age of
onset that coincides with the childbearing years. As over 20% of reproductive-age women
experience an episode of depression, identifying safe and effective treatments for depression
before, during and after pregnancy has become a critical public health issue. Historically,
pregnancy has been viewed as a protective time with respect to risk for psychiatric
illnesses, which has resulted in a lack of prospective systematic investigations on the
subject of acute treatment and prevention of MDD while women are planning to conceive and
during pregnancy. Contrary to previous assumptions, recent large-scale studies demonstrate
that new onset and recurrence of depressive episodes occur commonly during pregnancy and the
postpartum periods. The current standard of treatment for recurrent major depression is
maintenance antidepressant (AD) therapy, due to the high risk of recurrence among patients
who discontinue maintenance AD therapy.

Although ADs are frequently used during pregnancy, concerns remain regarding a spectrum of
adverse outcomes associated with fetal exposure to these medications including: increased
risk for teratogenicity compromised obstetrical outcomes and a variety of negative neonatal
clinical syndromes. Given these concerns, reproductive age women treated with AD frequently
elect to discontinue their medications proximate to pregnancy or immediately after becoming
pregnant despite the known increased risk for relapse or recurrence. With the exception of
observational data that demonstrate that women who discontinue medication around the time of
conception are at high risk of recurrence, no previous studies are available to inform
clinical treatment regarding medication discontinuation for a planned pregnancy.

This leaves women who are successfully treated with ADs and want to become pregnant caught in
the difficult clinical dilemma of weighing the risks of fetal exposure to medication against
the potential impact of untreated maternal depression during pregnancy. Clinical decisions
are made even more complex by the fact that most studies are far from definitive in terms of
comparing the risks of in utero exposure to ADs to the risks of untreated antenatal mood
disorder. Given this level of uncertainty, many women and their health care providers would
welcome evidence-based non-psychotropic interventions as an alternative to ADs in order to
prevent recurrence in euthymic women with histories of MDD as they plan pregnancy. However,
the potential efficacy of non-psychotropic interventions for this population has not been
systematically investigated.

There is consistent and growing evidence of a role for various folate forms in the prevention
and treatment of depression. In fact, there is compelling evidence that treatment with a
methylfolate agent would not only avoid the potential risks of antidepressants in pregnancy,
but would also confer important benefits to pregnancy and child outcomes as well, such as
prevention of major birth defects and longer term neurodevelopmental outcomes. To date, there
is an evidence base for antidepressant effects for folic acid, folinic acid, and
methylfolate, and similar findings may be attributable to the fact that these folate forms
share an interconversion potential in the complex set of pathways that comprise the
one-carbon cycle. These reactions, which in turn depend on B12 and homocysteine availability,
are postulated to exert an antidepressant effect by impacting the synthesis of
neurotransmitters such as norepinephrine, dopamine, and serotonin.

Some but not all studies suggest efficacy of folate monotherapy for MDD, but this
intervention may be limited by the common occurence of polymorphisms in the general
population that make folate a less efficient one-carbon cycle constituent than
L-methylfolate. Since certain polymorphisms that impair methylation processes and the
conversion of folate into its active form, methylfolate, have been found to be
overrepresented in individuals with depression, methylfolate may be a more effective form of
folate supplementation to target MDD. Also, methylfolate may be more readily absorbed in the
brain compared to other folate forms.

Recently, Fava and colleagues demonstrated that L-methylfolate is significantly superior to
placebo for the treatment of major depressive disorder in patients who had failed to respond
to AD therapy alone. In addition, several other open and blinded studies of methylfolate
monotherapy in a variety of depressed populations have found that patients experienced
significant improvement in depressive symptoms with no drug-related adverse events. Although
more controlled data are needed, initial studies indicate that methylfolate may be a safe and
effective option for the treatment of depression, especially in populations that are
vulnerable to medication-related adverse events, and those who are folate deficient or whose
folate needs are elevated, such as the case in pregnant women.

EnBrace HR is a prescription prenatal/postnatal dietary management product that contains
vitamins and minerals, including folic acid and methylfolate. It meets the above criteria as
a potential ideal candidate for the prevention of depression in pregnancy. It contains
L-methylfolate and other folate derivatives, and is optimal for a population with high rates
of polymorphisms that affect folic acid metabolism. It also contains omega-3 fatty acids,
primarily eicosapentaenoic acid, which shows promise for the treatment of depression.
Importantly, these components are crucial for healthy pregnancies. Folic acid supplementation
has been associated with the reduced risk of neural tube defects and is recommended for use
in women of reproductive potential to reduce the risk of birth defects, although a
substantial proportion of the population are poor folic acid metabolizers. Methylfolate
compounds specifically may provide a more efficient delivery of folate-related compounds to
this end.

Very few studies have examined treatments specifically to assist patients that discontinue
ADs, and none have examined this during the time proximate to attempts to conceive, or during
pregnancy, which is particularly relevant due to safety concerns. The adaptation of a
non-psychotropic treatment, such as EnBrace, for use in women who are planning pregnancy or
who are pregnant who choose to discontinue maintenance AD treatment would broaden treatment
choices available during this important time in the female life-cycle.

Objective: The overarching goal of this investigation is to assess EnBrace as a treatment for
the acute treatment and prevention of depression in women with a history of major depressive
disorder who decide to avoid or discontinue their maintenance AD treatment for pregnancy.
After completing this protocol, we plan to use the preliminary data for the development of a
randomized controlled trial protocol. We will include two groups of women who are interested
in minimizing medication exposures while trying to conceive or during pregnancy: 1) women who
have histories of depression and are not depressed, and would like to stop antidepressants
for pregnancy, 2) women in depressive episodes who are pregnant or trying to conceive (on or
off of antidepressant medications).

Specific Aim 1a: To evaluate the efficacy of EnBrace when used as maintenance treatment for
MDD in a group of women (N=10) who are trying to conceive or are early in pregnancy and who
have decided to stop ADs (Group 1). Relapse rates for women in this context have been
demonstrated to be high, with 68% relapse rates in a large multisite NIMH-funded trial.

Specific Aim 1b: To evaluate the efficacy of EnBrace when used as an acute treatment for MDD
in a group of women (N=10) who are trying to conceive or are early in pregnancy (Group 2).
Women will have major depressive episodes in this group, and may receive EnBrace as
monotherapy, or as an adjunct to current pharmacotherapy.

Hypothesis 1a: We hypothesize that relapse rates will be lower for women who receive EnBrace
compared to historical controls. MDD relapse will be determined by the Mini-International
Neuropsychiatric Interview (MINI) mood module that will be administered by a study clinician
at each visit.

Hypothesis 1b: We hypothesize that the majority of women who receive EnBrace will experience
a response (50% improvement in depressive symptoms) to EnBrace therapy.

Specific Aim 2: To identify biological markers as potential predictors of response to
EnBrace.

Hypothesis 2: We hypothesize that pre- to post-treatment changes in homocysteine, folate,
B12, IL-6 and CRP will be associated with response to EnBrace. We hypothesize specifically
that levels of folate and B12 will increase and homocysteine will decrease temporally with
treatment and be predictive of prevention of depressive episodes. We hypothesize that
treatment will lower IL-6 and CRP levels due to the anti-inflammatory components of EnBrace
(i.e., omega-3 fatty acids) and that decreased levels of inflammatory markers may predict
lower risk of depressive relapse in participants who enter the study while not on a
depressive episode (Group 1), and will predict response to treatment in women who enter the
study while in a depressive episode (Group 2).

Specific Aim 3 (Exploratory): To identify factors influencing adherence to and tolerability
of treatment. This will be achieved by using qualitative methods to explore (a) perceived
risks and benefits of treatment; (b) perceived side effect profile; (c) treatment
convenience; (d) knowledge of, attitudes towards, and preferences for depression treatment
while attempting to conceive or early pregnancy.

Hypothesis 3: We hypothesize that EnBrace will be perceived by patients as 1) an acceptable
and attractive treatment with a favorable risk/benefit profile in the context of pregnancy or
while trying to conceive, 2) well tolerated, 3) convenient and easy to adhere to, 4) will be
a treatment that women who are trying to conceive or who are pregnant find intuitive and
preferable to prescription antidepressant medication (or for women on antidepressant
treatment in Group 2, who prefer the augmentation with EnBrace rather than an increase in
antidepressant dose or augmentation with a prescription psychotropic medication).

Inclusion Criteria:

Group 1 (Observational, not-randomized)

Inclusion Criteria:

1. Planning pregnancy or pregnant < 28 weeks gestation

2. Currently meet criteria for stable remission from MDD, defined as a baseline score of
< 10 on the Montgomery-Åsberg Depression Rating Scale (MADRS)

3. Current or recent treatment with an AD

4. Have elected to discontinue AD medication for pregnancy (may have already begun or
completed taper)

5. Have a history of a major depressive episode/ Previous Episode of MDD, as verified
using the MINI Structured Clinical Interview for DSM-5; have MDD as one of their
primary diagnoses

6. Has a treating prescribing clinician for the treatment of MDD

Exclusion Criteria:

1. Current major depressive episode, as diagnosed on the MINI mood portion

2. Significant risk for self-harm or harm to others

3. Psychotic symptoms

4. Meeting criteria for a primary diagnosis of schizophrenia, an active eating disorder,
dementia, delirium, or other cognitive disorder

5. Presence of an active substance and/or alcohol abuse disorder within six months prior
to screening

6. Pernicious anemia or history of gastric bypass surgery

7. Seizure disorder and/or on anticonvulsant medications

8. Allergy to beeswax, soy, fish, nuts, peanuts, egg, wheat, milk, and/or shellfish

9. Non-English speaking

Group 2

Inclusion Criteria:

1. Planning pregnancy or pregnant < 28 weeks gestation

2. Currently experiencing clinically significant depressive symptoms, defined as a
baseline score of > 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS)

3. Experiencing a major depressive episode, as verified using the MINI Structured
Clinical Interview for DSM-5; have MDD as one of their primary diagnoses

4. Has a treating prescribing clinician for the treatment of MDD

Exclusion Criteria:

1. Significant risk for self-harm or harm to others

2. Psychotic symptoms

3. Meeting criteria for a primary diagnosis of schizophrenia, an active eating disorder,
dementia, delirium, or other cognitive disorder

4. Presence of an active substance and/or alcohol abuse disorder within six months prior
to screening

5. Pernicious anemia or history of gastric bypass surgery

6. Seizure disorder and/or on anticonvulsant medications

7. Allergy to beeswax, soy, fish, nuts, peanuts, egg, wheat, milk, and/or shellfish

8. Non-English speaking